La strategia terapeuticaadiuvante

Giuseppe MalinverniAnnalisa Rossi

S.C. RADIOTERAPIA ONCOLOGICA

A.O “ORDINE MAURIZIANO”TORINO

RadioterapiaRadioterapia AdiuvanteAdiuvante e e TumoriTumori delldell’’EndometrioEndometrioCheChe CosaCosa SappiamoSappiamo

• L’ 80% circa è diagnosticato in stadio I, il 13% in stadio II, e la sopravvivenza globale (OS) a 5 anni è elevata, 88% nella malattia in stadio I

• Un sottogruppo di pazienti con malattia in stadio I ha una riduzione significativa della OS a 5 anni, sulla base di diversi fattori prognostici, come lo stadio IC grado 3 che ha solo il 66% di OS

Uterine Cancer Staging System5562 pts- FIGO 1988 – 5y survival

Stage I: Stage I: 8080--90%90%AA G123, limited to G123, limited to endometriumendometriumBB G123, invasion < 50% G123, invasion < 50% myometriummyometriumCC G123, invasion > 50% G123, invasion > 50% myometriummyometriumStage II: Stage II: 6565--75%75%AA G123, G123, endocervixendocervix glands onlyglands onlyBB G123, G123, endocervixendocervix stromastromaStage III: Stage III: 3030--60%60%AA G123, (+) G123, (+) serosaserosa/ / adnexaadnexa /washings/washingsBB G123, (+) vaginaG123, (+) vaginaCC G123, (+) pelvic, PAN nodesG123, (+) pelvic, PAN nodesStage IV: Stage IV: 1515--25%25%AA G123, (+) GI, GU mucosa G123, (+) GI, GU mucosa BB G123, distant G123, distant metsmets, + groin nodes, + groin nodes

Uterine Cancer Staging System. FIGO 2010FIGO Annual Report on 42.000 pts - 5y survival

Pecorelli S, Int J Gynecol Obstet 2009; 103-104

Stage I: Stage I: 7575--90% 90% (1988 80(1988 80--90%)90%)AA G123, invasion < 50% G123, invasion < 50% myometriummyometrium: : 88% 88% BB G123, invasion > 50% G123, invasion > 50% myometriummyometrium: : 75%75%Stage II: Stage II: 70% 70% (1988 65(1988 65--75%)75%)

G123, G123, endocervixendocervix stromastromaStage III: Stage III: 4545--60% 60% (1988 30(1988 30--60%)60%)AA G123, (+) G123, (+) serosaserosa/ / adnexaadnexa: : 58%58%BB G123, (+) vagina/G123, (+) vagina/parametriumparametrium: : 50%50%CC G123, (+) nodes: G123, (+) nodes: 47%47%

IIIC1: (+) pelvic nodesIIIC1: (+) pelvic nodesIIIC2: (+) PAN nodesIIIC2: (+) PAN nodes

Stage IV: Stage IV: 1515--20% 20% (1988 15(1988 15--25%)25%)AA G123, (+) GI, GU mucosa: G123, (+) GI, GU mucosa: 17%17%BB G123, distant G123, distant metsmets, + groin nodes: , + groin nodes: 15%15%

Radioterapia Adiuvante e Tumori dell’EndometrioChe Cosa Sappiamo

• Fattori prognostici di rischio per recidiva– Età

– LVSI (invasione degli spazi vascolo-linfatici)

– Profondità di invasione miometriale

– Tipo istologico

– Grado 3

– LFN

– Diametro tumorale (< 2 cm vs ≥ 2 cm)

La radioterapia pelvica è indicata negli Stadi I in presenza di almeno 2 o 3 fattori di rischio: invasione miometriale profonda (≥50% dello spessore del miometrio), grado 3, ed età ≥60 anni

712

45

33

1 0,505

101520253035404550

OssBRTVRTERTE+BRTVRTA32 P

Naumann RW et al - Gynecol Oncol 75, 1999

St. I C G3 ESSSt. I C G3 ESS

RT ADIUVANTE NEL CARCINOMA ENDOMETRIALERT ADIUVANTE NEL CARCINOMA ENDOMETRIALEQUESTIONARIO SGO QUESTIONARIO SGO -- 19991999

90 %

CARCINOMA DELLCARCINOMA DELL’’ ENDOMETRIOENDOMETRIO

FREQUENZA PER CLASSE FREQUENZA PER CLASSE DIDI RISCHIO E RISCHIO E

RISCHIO RISCHIO DIDI RECIDIVARECIDIVA

Lukka H et al - Gynecol Oncol 102: 361, 2006 (mod)

Rischio rec loc basso 2- 4%

Rischio rec locoregionale 4-20%

Rischio rec locoregionale +/- a distanza >20%

Key Questions• How to define Risk Groups in EC in order to adequately

tailor therapy?– Low risk

–– Intermediate/Low, Intermediate and Intermediate/Hig hIntermediate/Low, Intermediate and Intermediate/Hig h

– High risk

• What is the Level of evidence regarding Adjuvant Therapy?

– Level I: Randomized Control Trials

– Level II evidence: Non-randomized, retrospective data

• What have we learned from 1000’s pts enrolled in clinical trials?

Patient Selection, Type of therapy, Patient Selection, Type of therapy, Outcome, QOL, CostOutcome, QOL, Cost

RT ADIUVANTE NEL CARCINOMA RT ADIUVANTE NEL CARCINOMA ENDOMETRIALEENDOMETRIALE

– Is it there a role for EBRT or VBT in early

stage radically resected endometrial cancer?

– Is it there a role for VBT alone in low

and/or medium risk early stage endometrial cancer?

– Does VBT +/- EBRT play a significant role

in the adjuvant treatment of intermediate

and high risk endometrial cancer

CRTBT

GOG #122 - 2006

NSGO - EORTC - 2007

J - GOG - 2008

IT - CNR - 2006

ASTEC - NCIC - 2009

GOG #99 - 2004

PORTEC-2 - 2008

PORTEC-1 - 2000

Aalders - 1980

CHEB+BTEBNFT

Sorbe - 2009

ADJUVANT TREATMENT OF ENDOMETRIAL CANCER:randomized trials - Low - Intermediate Risk

IR

HR

LR

• 645 PTS• TAH+BSO +/- PLND

RANDOM

NFT

BT

ADJUVANT TREATMENT OF ENDOMETRIAL CANCER: Sorbe - 2009

• Stage– IA-B – G1-2

• endometrioid

Sorbe B et al. Int J Gynecol Cancer;19:873, 2009

LR 100%median FU 68 months Low Risk100%

n s94.7%95.1%OS

n s2.9%0.9%tox G2

n s0.3%0.9%Pel Rec

n s1.2%3.1%Vag Rec

pVBTNFT• local control improved in

BT arm, not significantly

• OS rate not different

• No G3 toxicity

ADJUVANT TREATMENT OF ENDOMETRIAL CANCER: Sorbe - 2009 Sorbe B et al. Int J Gynecol Cancer;19:873, 2009

• Results– LRR, 2.6%; distant mets 2.1%– Vaginal recurrences, 3% vs 1%– 2.8% grade 1-2 toxicity with IVB

• No benefit of adjuvant RT in the low-risk group

CRTBT

GOG #122 - 2006

NSGO - EORTC - 2007

J - GOG - 2008

IT - CNR - 2006

ASTEC - NCIC - 2009

GOG #99 - 2004

PORTEC-2 - 2008

PORTEC-1 - 2000

Aalders - 1980

CHEB+BTEBNFT

Sorbe - 2009

ADJUVANT TREATMENT OF ENDOMETRIAL CANCER: randomized trials - Intermediate Risk

IR

HR

LR

PORTEC: Patterns of RecurrenceCreutzberg et al, Lancet 2000; 355: 1404-1411Creutzberg et al. Gynecol Oncol 2003; 89: 201

Site of FailureSite of Failure Surgery Surgery + EBRT+ EBRT NFTNFT

LocoregionalLocoregionalfailure failure 4%4%

15%, 15%, P< 0.0001P< 0.0001

VaginaVagina 2 %2 % 10%10%

PelvisPelvis 2%2% 5%5%

Distant failureDistant failure 10%10% 6%6%

Death from ECDeath from EC

LRRLRRDistant MetsDistant Mets

10%10%

1%1%8%8%

7.5%7.5%

2%2%5%5%

NonNon --EC DeathEC Death

NonNon --ECEC22ndnd cancerscancers

14%14%5%5%

11%11%5%5%

P< 0.0001P< 0.0001

8-year Actuarial Rate

73% of the recurrenceslimited to the vagina

No RT

• 392 PTS• TAH+BSO & PLND

RANDOM

observation

EBR 50.4 Gy

ADJUVANT TREATMENT OF ENDOMETRIAL CANCER: GOG #99 - 2004

L I R66%

H I R *34%

Stage IB - IC - II (occult)

Keys HM et al. Gynecol Oncol 92:744,2004

∗ age G2 - G3 LVSI M>50%

0.0010.00114%5.5%tox >G2

0.592%86%OS

0.0010.00198%91%LC

pEBRNFT • adjunctive RT in early stage IR endometrial carcinoma decreases the risk of recurrence

• but should be limited to patients in HIR* group

• 905 PTS• TAH+BSO +/- PLND

RANDOM

NFT +/- BT

40-46 Gy EBR+/- BT

ADJUVANT TREATMENT OF ENDOMETRIAL CANCER: ASTEC - NCIC - 2009

L R1%

I R76%

H R23%

• Stage– IB G3 – IC – IIA

• endometrioid • SC/CC

Blake P. et al Lancet 373:137, 2009

over 50% in each group received IVB

Overall SurvivalOverall Survival Disease Disease –– Specific SurvivalSpecific Survival

No difference in OS or DSS with the addition of adjuvant EBRT

3% difference in the cumulative incidence of vaginal relapses –

BUT… over 50% in each group received IVB

MRC, ASTEC and NCIC CTG EN.5 TrialsLancet, 2009; 373: 137

• RTE postoperatoria non è indicata nelle pz a basso rischio

(età < a 60 anni e/o in stadio IB e con tumori G2 con

invasione superficiale)

• RTE postoperatoria riduce le recidive loco-regionali ma

non ha impatto significativo sulla sopravvivenza

• RTE postoperatoria incrementa la morbilità legata al

trattamento (14% vs 6%).

• RTE indicata nelle pazienti con alto rischio di recidiva

locale(LRR ≥ 10-15%)

What have we learned from these randomized trials regarding adjuvant therapy

in Intermediate-Risk EC patients?

Systematic review & Meta-analysisJohnson et Comes BJOG 2007; 114: 1313-20

Total 1864 pts Pelvic Total 1864 pts Pelvic recrec in EBRT 21/868 No EBRT 81/996in EBRT 21/868 No EBRT 81/996•• EBRT reduced LRR, RR 0.34 (p< 0.0001), in intermediate risk EC EBRT reduced LRR, RR 0.34 (p< 0.0001), in intermediate risk EC

with an absolute risk reduction of 5,25%with an absolute risk reduction of 5,25%–– No impact in survival from lower risk cancers or distant failureNo impact in survival from lower risk cancers or distant failuress

–– A potential survival advantage for about 10% with EBRT A potential survival advantage for about 10% with EBRT shuoldshuold be be considered in patients with multiple highconsidered in patients with multiple high--risk features, including risk features, including pStpSt 1C G31C G3

Systematic review & Meta-analysisA. Kong et al, Ann Oncol 2007; 18: 1595-1604

•• Total 1770 pts Pelvic Total 1770 pts Pelvic recrec in RT 21/870in RT 21/870 No RT 80/900No RT 80/900

•• EBRT reduced LRR, RR 0.28 (p< 0.0001), with an absolute EBRT reduced LRR, RR 0.28 (p< 0.0001), with an absolute risk reduction of 6%risk reduction of 6%–– No impact in death from all causes, ECNo impact in death from all causes, EC--deaths or distant failuresdeaths or distant failures

–– EBRT should be considered in patients with multiple highEBRT should be considered in patients with multiple high--risk features, risk features, including G3 and including G3 and pStpSt ICIC

• EBR greatly reduced locoregional recurrence, a RR

reduction of 72% (PORTEC)

• However, there is not a reduction in the risks of distan t

recurrence, death from all causes, and from EC.

• EBR has a trend toward reduction in the risks of death

from all causes and from EC for patients with multiple

high risk factors (G3 and stage Ic).

• EBR increases the risk of toxicity and should be

avoided in stage with low recurrence rate (Ia-b G1- 2 )

Kong A, et al. Cochrane Database 2007,

ADJUVANT TREATMENT OF ENDOMETRIAL CANCERCochrane review stage I - 2007

What is the role of IntracavitaryVaginal Brachytherapy Alone?

Advantages• Lower Cost• Lower Morbidity

– Minimal acute and long-term toxicity

• Patient convenience– Outpatient procedure– Limited number of

Treatments

• 95% relative reduction risk of vaginal recurrences

Disadvantages

• Does not address the pelvis

• Post-operative geometrical restrictions

• Vaginal shortening

ADJUVANT TREATMENT OF ENDOMETRIAL CANCER: PORTEC-2 - 2008

Nout RA J Clin Oncol, 26, 20S: 5503 2008

• 427 PTS• TAH+BSO no PLND

RANDOM

VBT21 Gy/3 fr

EBR 46 Gy/23 fr

I R100%

Stage • ICG1-2 - IBG3 > 60 y• IIA G1-2-3 M<50%

Primary endpoint: Vaginal Relapse Rate

Secondary: Quality of Life, Survival

PORTEC 2 trial Results

Outcome EBRT IVB P value

Vaginal Vaginal relapsesrelapses

1.9% 0.9% NS

LRRLRR 2.5% 4% NS

Pelvic Pelvic relapsesrelapses

0.6% 3.5% p = 0.03p = 0.03

Distant Distant relapsesrelapses

5.7% 6.3% NS

DFSDFS 89% 89% NS

OSOS 90% 90% NS

• Significantly decreased GI and toxicity with IVB

• Less impairment in daily activities

• Improved social functioning

• Overall, significant improvement in the QOL

QOL: EBRT QOL: EBRT vsvs IVBIVB

PORTEC 2 trial Conclusions

• Results of EBRT very comparable to EBRT in PORTEC-1

• Brachytherapy as effective as EBRT in preventing vaginal relapses and less toxic compared to EBRT

• QOL significantly better with brachytherapy

• More pelvic recurrences after brachytherapy, but mostly in combination with distant relapse (first failure 1.3 vs 0.7%)

• No differences in DFS (89%) and OS (90%)

CRTBT

GOG #122 - 2006

NSGO - EORTC - 2007

J - GOG - 2008

IT - CNR - 2006

ASTEC - NCIC - 2009

GOG #99 - 2006

PORTEC-2 - 2008

PORTEC-1 - 2000

Aalders - 1980

CHEB+BTEBNFT

Sorbe - 2009

ADJUVANT TREATMENT OF ENDOMETRIAL CANCER: randomized trials - High Risk

IR

HR

IT - CNR - 2006 Maggi R et al. Br J Cancer 95: 266, 2006

J-GOG - 2008 Susumu N at al. Gynecol Oncol, 108: 226,2008

NSGO - EORTC - 2007 Hogberg T et al, ASCO 2007

GOG #122 - 2006 Randall M et al. JCO 24:36, 2006

ADJUVANT TREATMENT OF ENDOMETRIAL CANCER: randomized trials - High Risk

EBRT vs CT

EBRT vs CT

EBRT vs CRT

Conclusions of the Role of Chemotherapy in HR EC

•• NessunaNessuna conclusioneconclusione definitvadefinitva puòpuò essereessere trovatatrovata in in

considerazioneconsiderazione deidei varivari critericriteri didi inclusioneinclusione neinei trial trial

disponibilidisponibili didi RCT’sRCT’s

•• La La chemoterapiachemoterapia è è efficaceefficace solo solo nell’analisinell’analisi didi alcunialcuni

sottogruppisottogruppi didi pazientipazienti..

•• Il Il tassotasso didi ricadutaricaduta è simile a è simile a quelloquello dell EBRT (~ 15dell EBRT (~ 15--

20%) ed 20%) ed ilil 50% 50% didi questequeste è è confinataconfinata in in ambitoambito pelvicopelvico

•• SonoSono quindiquindi necessarinecessari adeguatiadeguati trial trial cliniciclinici disegnatidisegnati susu

gruppigruppi didi rischiorischio benben definitidefiniti ed ed emogeneiemogenei per per poterpoter

miglioraremigliorare l’outcomel’outcome in in questaquesta popolazionepopolazione didi pazientipazienti

PORTEC-3Concurrent and adjuvant CT vs RT alone

• N= 800 pts

• FIGO IB G3 (+) LVSI, St IC-IIA G3, St IIB, IIIA, II IC any

grade, IB-III UPSC or CCC, after TAH-BSO +/- LND

• Randomization

– Control arm: Pelvic RT

– Experimental arm: [RT+ weekly CDDP] + 4 courses

CDDP+Taxol

– Primary endpoint: OS and DFS Enrollmentongoing

La maggior parte delle recidive locoregionali sono a livello

vaginale, (soprattutto sulla cupola): Il tasso di controllo

nelle pazienti sottoposte a EBRT varia dal 40–80%

ENDOMETRIAL CANCERthe problem of the local control

OS (3yr)

Jhingran A, IJROBP, 56:1366, 2003 (modif)

ENDOMETRIAL CANCERsurvival after vaginal recurrence

La ricaduta locale ed il successivo trattamento con possibili effetti collaterali provocano ansia e elevato stress, enfatizzando la necessità di un massimo controllo locale al primo trattamento

Considerando l’alto rischio per questo tipo dipazienti con recidiva locala e/o regionale, il dato

sul controllo definitivo si attesta sul ~ 50%

Immediate vs Delayed RT?

• Probabilmente il tasso di controllocomplessivo (overall control rate) è inferiore a quello stimato [>70%]

• Le recidive con il solo solo coinvolgimentocoinvolgimento delladellamucosa mucosa vaginalevaginale, possono essere guarite nel70% dei casi con EBRT+/-IVB con unatossicità di grado 3-4 del of 5-10%

Cost-effectiveness of adjuvant RT in Intermediate Risk Endometrial cancer

N.C. Rankins et al. Gynecol Oncol, 2007; 106: 388-393

Costi ragionevoli nelle pazienti a rischio intermedio e intermedio-alto

• RTE postoperatoria incrementa la morbilitàlegata al trattamento

• Complicanze: 25% RT vs 6% no RT

– 66 % di grado 1; 2% di grado 3-4,

June 1990 Dec 1997

RT Technique

• AP-PA: 101 pts

• 3 fields: 61 pts

• Box: 176 pts

PORTEC: MorbilityCreutzberg et al, Lancet 2000; 355: 1404-1411Creutzberg et al. Gynecol Oncol 2003; 89: 201

162

EBRT in GINECOLOGIA

OTTIMIZZAZIONE DELLA RADIOTERAPIA

POSTOPERATORIA

2D ���� 3D

Vecchia Radioterapia Basata su reperi ossei

Da dimenticare !!

IJROBP 1999

Uso dell’imaging x ottimizzazione della RT

PTV

Ginecologia: planning 2D

■ 30% omissione geografica (“tecnica box”)

Kim, IJROBP, 31, 1995

■ 10% omissione geografica LL e CranialePendlebury IJROBP 1993 – Zunino IJROBP 1992

� 32 % sottodosaggio regionale

Russell IJROBP, 23, 1992

■ 45% sottodosaggio LN iliaci esterni

Bonin IJROBP, 34, 1996

A margini inadeguati

corrisponde un mancato

controllo locale

PTVPTV

Contouring su immagini TC e/o RM per evitare ….Imaging TC e RMTarget Missing !!

EBRTproblematiche

Sistemi di immobilizzazione

Quale tecnica?

R&O 2001

Supino

PronoBellyboard

Dislocazione delle anse intestinali

CARCINOMA CARCINOMA

ENDOMETRIALEENDOMETRIALE

RT PELVICA RT PELVICA

ADIUVANTE ADIUVANTE

bellybelly boardboard

Vescica Piena

Vescica Vuota

Vescica Vuota

Rischio di spostamento dell’intestino all’interno del campo di trattamento

Riduzione dei margini Riduzione dei margini

IMRT = Quale obiettivo?IMRT = Quale obiettivo?

Riduzione Volume di Riduzione Volume di

trattamentotrattamento

Risparmio OARRisparmio OAR

Modern treatment techniques IMRT

Dose escalationDose escalation

Perché IMRT in Ginecologia?

• Copertura omogenea del Target• Riduzione del volume irradiato di ileo di un

fattore 2• Riduzione del volume di retto e vescica irradiati

del 23%• Riduzione della tossicità enterica• Riduzione della tossicità midollare

Roeske: IJROBP 49, 2000Mundt: Med Dosim 27, 2002Lujan: IJROBP 57, 2003 Brixey: IJROBP 52, 2002

V95

IMRTBOX

↓ tossicità enterica

Roeske: IJROBP 49, 2000 - IJROBP 56, 2003

• ↓↓↓↓ dell’uso della richiesta di farmaci dal 75 % nel gr uppo

RT convenzionale al 34 % con IMRT (p= 0.001)

↓ Tossicità midollare

• ↓ midollo osseo irradiato (- 40%)• ↑ tolleranza ematologica CT concomitante

Lujan AE et al.: IJROBP 57, 2003 Brixey IJROBP 52, 2002

SIB ipofrazionato

adjuvant RT improves the LC in IR with toxicity

EBRT is better than BT in IR but the benefit is

small and the morbidity is higher

ADJUVANT TREATMENT OF ENDOMETRIAL CANCER:ADJUVANT TREATMENT OF ENDOMETRIAL CANCER:

Take home messages

No benefit of adjuvant RT in the low-risk group

the association RT + CHT might be superior to RT in HIR and HR, but is more toxic

no prospectic studies of concurrent chemo-RT closed at present

chemotherapy is better than a suboptimal RT in HR pts

� Use Modern Radiotherapy !!!

ADJUVANT TREATMENT OF ENDOMETRIAL CANCER:ADJUVANT TREATMENT OF ENDOMETRIAL CANCER:

Take home messages

Grazie per l’attenzione